Neural Markers of Resilience in Adolescent Females at Familial Risk for Major Depressive Disorder

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1 Reserch JAMA Psychitry Originl Investigtion Neurl Mrkers of Resilience in Adolescent Femles t Fmilil Risk for Mjor Depressive Disorder Adin S. Fischer, MD, PhD; M. Ctlin Cmcho, BA; Tiffny C. Ho, PhD; Susn Whitfield-Gbrieli, PhD; In H. Gotlib, PhD IMPORTANCE Adolescence is neurodevelopmentl period during which experiencedependent plsticity in brin circuitry my confer vulnerbility to depression s well s resilience to disorder. Little is known, however, bout the neurl mechnisms tht underlie resilience during this criticl period of brin development. Invited Commentry Supplementl content OBJECTIVE To exmine neurl functionl connectivity correltes of resilience in dolescent femles t high nd low fmilil risk for depression who did nd did not develop the disorder. DESIGN, SETTING, AND PARTICIPANTS A longitudinl study ws conducted t Stnford University from October 1, 23, to Jnury 31, 217. Sixty-five femle dolescents prticipted in the study: 2 t high risk in whom depression did not develop (resilient), 2 t high risk in whom depression developed (converted), nd 25 t low risk with no history of psychopthology (control). MAIN OUTCOMES AND MEASURES We compred functionl connectivity between resilient nd converted, nd between resilient nd control, dolescent femles using voxelwise 2-sided t tests to exmine neurl mrkers of resilience to depression s the min outcomes of interest. Specificlly, we ssessed differences in connectivity of the limbic (mygdl seed), slience (nterior insul seed), nd executive control (dorsolterl prefrontl cortex seed) networks, implicted in emotion regultion. We lso exmined the ssocition between functionl connectivity nd life events. RESULTS Of the 65 prticipnts (men [SD] ge, 18.9 [2.5] yers), dolescent femles in the resilient group hd greter connectivity between the mygdl nd orbitofrontl cortex (z score =.23; P <.1) nd between the dorsolterl prefrontl cortex nd frontotemporl regions (z score =.24; P <.1) thn did converted dolescent femles. In dolescent femles in the resilient group only, strength of mygdl-orbitofrontl cortex connectivity ws correlted with positive life events (r 18 =.48; P =.3). Resilient dolescent femles hd greter connectivity within frontl (z score =.7; P <.1) nd limbic (z score =.21; P <.1) networks thn did control individuls. Both high-risk groups hd greter slience network connectivity: the converted group hd greter intrnetwork connectivity thn did the resilient (z score =.13; P <.1) nd control (z score =.1; P <.1) groups, nd the dolescent femles in the resilient group hd greter slience network connectivity with the superior frontl gyrus thn did the converted (z score =.24; P <.1) dolescent femles. CONCLUSIONS AND RELEVANCE Resilient dolescent femles hve compenstory functionl connectivity ptterns in emotion regultory networks tht correlte with positive life events, suggesting tht experience-dependent plsticity within these networks my confer resilience to depression. Further studies re wrrnted concerning connectivity-ssocited trgets for promoting resilience in high-risk individuls. JAMA Psychitry. doi:1.11/jmpsychitry Published online Mrch 21, 218. Author Affilitions: Deprtment of Psychology, Stnford University, Stnford, Cliforni (Fischer, Ho, Gotlib); Deprtment of Psychitry nd Behviorl Sciences, Stnford University, Stnford, Cliforni (Fischer); Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvni (Cmcho); Deprtment of Brin nd Cognitive Sciences, Msschusetts Institute of Technology, Cmbridge (Whitfield-Gbrieli). Corresponding Author: Adin S. Fischer, MD, PhD, Deprtment of Psychitry nd Behviorl Sciences, Stnford University, 41 Qurry Rd, Ste 224, Stnford, CA (dinf@stnford.edu). (Reprinted) E1

2 Reserch Originl Investigtion Neurl Mrkers of Resilience in Adolescent Femles t Risk for Mjor Depressive Disorder An estimted 1 in 3 dolescent femles in the United Sttes is dignosed s hving mjor depressive disorder (MDD), 1 the leding cuse of disbility nd second leding cuse of deth during dolescence, 2 with n estimted 17% lifetime prevlence. 3 In contrst to the lrge body of reserch exmining neurl spects of depression in dolescents, 4,5 little is known bout neurobiologicl fctors tht confer resilience to this disorder. The Americn Psychologicl Assocition defines resilience s the process of dpting well in the fce of significnt sources of stress nd bouncing bck from difficult life experiences. 6 Debte is ongoing bout the definition nd determinnts of resilience, which likely include biologicl, psychologicl, socil, nd culturl fctors tht help shpe response to stressful experiences. 7 Extending the focus of psychopthology-bsed models to incorporte strength- nd competency-bsed pproches my fcilitte the development of strtegies designed to prevent nd tret dolescent depression s well s promote resilience in high-risk youth. Adolescence is mrked by stress nd incresed risk for the onset of depression 3 ; it is lso neurodevelopmentl period with the potentil for heightened lerning, flexibility, nd development of dptive emotion regultion skills. 8,9 Significnt mturtion of neurl networks involved in emotion regultion 1,11 nd experience-dependent plsticity within brin networks 12 occur over dolescence. Emotion dysregultion in dolescents hs been ssocited with nomlies in the limbic network, the executive control network, 16 nd the slience network. 17 Moreover, reserchers hve found incresed plsticity within emotion regultion circuitry fter tretment with ntidepressnts nd psychotherpy, first-line interventions for dolescent depression Specificlly, bnormlly decresed prefrontl ctivity, implicted in deficits in emotion regultion nd cognitive control in depression, 21,22 normlizes with successful tretment in individuls with depression Reserchers hve lso documented chnges in connectivity between the mygdl (within the limbic network) nd the nterior insul (within the slience network), 19,23 s well s in executive control network connectivity, fter psychotherpy. While these tretment-induced chnges in connectivity re not necessrily mrkers of resilience, they re promising trgets for puttive networks implicted in neurl mechnisms underlying resilience to developing dolescent depression. The present study ws designed to exmine resilience in dolescent femles t fmilil risk for depression. Using seedbsed resting-stte functionl mgnetic resonnce imging (fmri) pproch, we compred functionl connectivity of the limbic network, executive control network, nd slience network in high-risk dolescent femles in the resilient group with both high-risk dolescent femles in whom depression developed (converted) nd low-risk dolescent femles with no history of psychopthology (control) group. Bsed on previous findings, 24,25 we hypothesized tht compred with their conversion nd control peers, dolescent femles in the resilient group will show dptive compenstory chnges in their brin networks, including greter connectivity between the mygdl nd prefrontl regions implicted in emotion regultion, Key Points Question Wht re neurl mrkers of resilience in dolescent femles t risk for depression? Findings In this longitudinl study of 65 dolescent femles, we exmined functionl connectivity in limbic, slience, nd executive control networks. High-risk dolescent femles who were resilient to depression hd greter connectivity between regions in limbic nd executive control networks thn did high-risk dolescent femles who developed depression nd low-risk control dolescents; further, the strength of this connectivity ws correlted with positive life events in the group of resilient dolescent femles. Mening Our findings highlight functionl neuroimging biomrkers of resilience to dolescent depression tht my be cndidte trgets for the prevention nd tretment of depression. nd greter overll executive control network connectivity. We lso hypothesized tht the converted group will show reduced executive control network nd greter slience network connectivity compred with the resilient nd control groups. Finlly, given the modultory roles of significnt life events on brin development, 26 we exmined whether greter mygdl-frontl connectivity is ssocited with these significnt life events. Methods Study Design This longitudinl study of fmilil risk for depression recruited 19 femle dolescents. Dt were collected t Stnford University from October 1, 23, to Jnury 31, 217. Prticipnts were followed over the course of dolescence from ge 9 through ge 18 yers, for men (SD) of 7.6 (2.4) yers, nd completed clinicl nd behviorl ssessments t 18- month intervls. The neuroimging dt were cquired towrd the end of the study, t 1 time (men [SD] ge 18.9 [2.5] yers of prticipnts when neuroimging dt were cquired). The study ws pproved by the institutionl review bord t Stnford University; written ssent ws obtined from ll study prticipnts nd written consent ws obtined from their prents. Prticipnts At the time of study entry, prticipnts were between 9 nd 14 yers of ge nd hd no current or lifetime history of ny Axis I disorder. Hlf of the prticipnts hd mother who hd recurrent MDD episodes during the dughter s lifetime (high risk); the other hlf hd mothers with no history of Axis I disorder (low risk). Approximtely 6 yers fter entering the study, 92 of the 19 prticipnts (43 high-risk dolescent femles; 49 low-risk dolescent femles) completed resting-stte functionl mgnetic resonnce imging (fmri) scn. We report here on 65 of these 92 dolescent femles: 2 high-risk femles in whom MDD developed fter entry to the study but who no longer hd MDD by the time of the scn (converted); 2 high-risk E2 JAMA Psychitry Published online Mrch 21, 218 (Reprinted) jmpsychitry.com

3 Neurl Mrkers of Resilience in Adolescent Femles t Risk for Mjor Depressive Disorder Originl Investigtion Reserch Figure 1. Limbic Network Connectivity A Bilterl mygdl seeds C Functionl connectivity D Orbitofrontl cortex connectivity B Left orbitofrontl cortex t Vlue z Score LES, No. of Positive Events z Score A, Bilterl mygdl seeds (coordintes in Montrel Neurologicl Institute spce: left: 22, 5, 17; right: 22, 5, 17). B, Region of the left OFC tht hd greter connectivity with the limbic network (right mygdl seed) in RES s compred with CVT group. Color br represents t vlues from the between-group t test (RES>CVT). C, Box-nd-whisker plots of mygdl to OFC functionl connectivity (quntified s z score) for ech group. The horizontl line in the middle of ech box indictes the medin, while the top nd bottom borders mrk the 75th nd 25th percentiles, respectively. The whiskers bove nd below the box mrk the 9th nd 1th percentile. The points beyond the whiskers re outliers. D, Right mygdl to left OFC connectivity plotted ginst number of LES positive events within the RES group (r 18 =.48, P =.3). The shded re represents the 95% CI. CTL indictes control; CVT, converted; LES, Life Experiences Survey; OFC, orbitofrontl cortex; nd RES, high-risk resilient. P <.1 compred with CVT. femles in whom MDD did not develop (resilient); nd 25 lowrisk femles in whom no Axis I disorder developed (control). A more detiled description of smple selection is presented in eappendix 1 in the Supplement. Clinicl nd Behviorl Assessments At ech ssessment t 18-month intervls, interviewers dministered the Kiddie Schedule for Affective Disorders nd Schizophreni present nd lifetime version (K-SADS-PL) 27 to prticipnts who were younger thn 18 yers nd the Structured Clinicl Interview for DSM (SCID) 28 to prticipnts who were older thn 18 yers. Receiving dignosis of MDD required tht prticipnts meet DSM-IV criteri with no history of mnic, hypomnic, or mixed episodes. 29 In ddition to the K-SADS-PL nd SCID dministered t bseline nd follow-up visits, prticipnts completed the Children s Depression Inventory (CDI) 3 to ssess depressive symptomtology nd the Life Experiences Survey (LES) 31 to ssess positive nd negtive life events nd the perceived mening of these events. Prticipnts reported on the presence, vlence (positive or negtive), nd significnce (4-point scle; indicting no effect to 3 indicting gret effect) of 5 life events (eg, moving to new home, new reltionship, specil recognition t school, prent s divorce). The summed significnce score of ech event creted the cumultive negtive or positive impct score. Seed-Bsed Functionl Connectivity Anlyses The cquisition of fmri nd prmeters for preprocessing re described in eappendix 2 in the Supplement. We conducted resting-stte functionl connectivity nlyses using seeddriven pproch in Functionl Connectivity SPM Toolbox (CONN). 32 We selected whole-brin seed-to-voxel nlysis pproch to test priori hypotheses involving specific neurl networks, nd to fcilitte comprisons with the extnt restingstte fmri literture on dolescent MDD. 14,15,33,34 We generted whole-brin seed-to-voxel correltion mps by extrcting the residul Blood Oxygention Level Dependent (BOLD) signl time course from priori regions of interest, including the mygdl (limbic network), nterior insul (slience network), nd dorsolterl prefrontl cortex (executive control network) (Figure 1). Seed regions were 5 mm in dimeter nd creted bsed on pek coordintes from the literture We used methods tht minimize the influence of motion nd rtifct (eappendix 3 in the Supplement). We computed Person correltion coefficients between the time course of ech seed nd the time course of ll other voxels in the brin. We converted correltion coefficients to z scores using Fisher trnsformtion nd used them in second-level generl liner model nlyses to exmine group differences. We performed voxelwise 2-sided t tests to directly compre dt from prticipnts in the resilient group with dt from prticipnts in the conversion group nd dt from prticipnts in the resilient group with dt from prticipnts in the control group s the min outcomes of interest. For ll connectivity nlyses, we set voxellevel thresholds to P <.1 nd corrected for multiple comprisons using cluster-level flse discovery rte (FDR) thresholding P <.5 bsed on gussin field theory. 39 We pplied Bonferroni correction to the FDR-corrected clusterlevel P vlues to correct for 6 priori seeds (bilterl mygdl, nterior insul, nd dorsolterl prefrontl cortex). jmpsychitry.com (Reprinted) JAMA Psychitry Published online Mrch 21, 218 E3

4 Reserch Originl Investigtion Neurl Mrkers of Resilience in Adolescent Femles t Risk for Mjor Depressive Disorder Sttisticl Anlyses The nlyses were performed in SPSS softwre, version 23 (SPSS Corp) nd R pckge, version Sttisticl significnce ws set t 2-sided P <.5 for behviorl nd demogrphic dt. We compred the 3 groups on demogrphic, clinicl, nd behviorl ssessments using 1-wy nlysis of vrince with post hoc Tukey tests, s pproprite, for continuous vribles. We used the Wilcoxon signed rnk test to compre the 3 groups on income nd eductionl level, nd χ 2 tests to exmine group differences in rce/ethnicity nd mediction. We first used Person correltions to exmine the ssocition between mygdl-orbitofrontl cortex (OFC) functionl connectivity nd LES scores (positive nd negtive, seprtely) within ech high-risk group (resilient, converted). We then performed liner regression to test whether the highrisk groups differed in ssocitions between LES scores on mygdl-ofc functionl connectivity. We further tested tht LES scores were not correlted with motion prmeters. 4 Results Demogrphic nd Clinicl Informtion In totl, 65 femle dolescents were followed in this longitudinl study, ctegorized into 3 groups: 2 t high risk in whom depression did not develop (resilient), 2 t high risk in whom depression developed (converted), nd 25 t low risk with no history of psychopthology (control). Other demogrphic nd clinicl dt re presented in Tble 1. The 3 groups did not differ in ge t the time of the scn or recruitment, length of time in the study, rce/ethnicity, or household income. Although no prticipnt experienced psychitric disorder prior to entering the study, prticipnts in the high-risk groups hd higher CDI scores t bseline thn did the control group; however, the men CDI scores t study entry were well below the dignostic cutoff of score of 13. On the dy of the scn, the converted group hd higher CDI scores nd lower globl ssessment of functioning scores thn did the resilient nd control groups. Few of the prticipnts (n = 4) were tking psychotropic mediction t the time of the scn; the 3 groups did not differ on this vrible. Three resilient prticipnts hd lifetime history of lcohol nd cnnbis buse (n = 1), specific phobi (n = 1), or binge eting disorder (n = 1); ll prticipnts were in full remission t the time of the scn except for the prticipnt who met criteri for specific phobi whose score on the Beck Anxiety Inventory scle ws 4, well within the norml rnge (-9). Beck Anxiety Inventory scle scores rnge from to 63. A totl score of to 7 is interpreted s miniml level of nxiety; 8 to 15 s mild ; 16 to 25 s moderte, nd; 26 to 63 s severe. The resilient nd converted groups did not differ significntly with respect to the totl number of mternl episodes of depression (t 19 = 1.14; P =.27). Life Events nd Resting-Stte Functionl Connectivity Scores on the LES re summrized in Tble 1. The 3 groups did not differ in number of negtive or positive life events or in positive or negtive impct scores t the time of the scn. Results of the nlyses compring resilient vs converted nd results of comprisons between resilient nd control re summrized in Tble 2. Amygdl Seed Results Compred with the converted group, dolescent femles in the resilient group hd greter connectivity between the left mygdl nd right superior frontl gyrus (SFG) (z score =.19; P <.1), right mygdl nd left OFC (z score =.23; P <.1), nd bilterl inferior temporl gyri (z score =.16; P <.1). Compred with the control group, the resilient group hd greter bilterl mygdl connectivity with the left nd right ngulr gyri (z score =.9, P <.1). See Figure 1B nd C for more detils, nd Tble 2 for complete list of our results. Anterior Insul Seed Results Compred with the control group, both high-risk groups hd greter slience network connectivity: the converted group hd greter intrnetwork connectivity thn did the resilient (z score =.13; P <.1) nd control (z score =.1; P <.1) groups, nd the dolescent femles in the resilient group hd greter slience network connectivity with the superior frontl gyrus thn did the converted (z score =.24; P <.1) dolescent femles. See Figure 2 for more detils nd Tble 2 for complete list of our results. Dorsolterl Prefrontl Cortex Seed Results Compred with the converted group, dolescent femles in the resilient group hd greter left dorsolterl prefrontl cortex connectivity with the left inferior frontl gyrus (IFG) including the ventrolterl prefrontl cortex nd with the left superior temporl gyrus (STG) (z score =.24; P <.1). Compred with the control group, dolescent femles in the resilient group hd greter right dorsolterl prefrontl cortex connectivity with the right MFG (z score =.7; P <.1). See Figure 3 for more detils nd Tble 2 for complete list of our results. Differentil Effects of Life Events on Amygdl-OFC Connectivity No significnt correltions between mygdl-ofc functionl connectivity were found with negtive events, mening of negtive events, or mening of positive events within either high-risk group. We found significnt correltion between positive life events nd connectivity between right mygdl nd left OFC in the resilient (r 18 =.48; P =.3) but not in the converted (r 18 =.18; P =.47) groups. We compred these ssocitions between the high-risk groups directly using liner regression, which yielded significnt interction effect of group nd positive life events on mygdl- OFCFC(t 35 = 2.9; P =.4). The LES scores were not significntly correlted with ny of the 18 motion prmeters in the resilient group. Supplementl Anlyses Given significnt group differences in CDI nd mternl Wechsler Adult Intelligence Scle scores, we included these mesures s covrites (seprtely) to confirm tht these group differences did not drive our findings (eappendix 4 in the Supplement). E4 JAMA Psychitry Published online Mrch 21, 218 (Reprinted) jmpsychitry.com

5 Neurl Mrkers of Resilience in Adolescent Femles t Risk for Mjor Depressive Disorder Originl Investigtion Reserch Tble 1. Demogrphic Informtion nd Clinicl Dt Vrible CTL (n = 25) RES (n = 2) CVT (n = 2) Sttisticl Vlue P Vlue Demogrphic Informtion Age t scn, men (SD), y (2.61) (2.62) (2.5) F 2,62 =.5.95 Age t study entry, men (SD) (1.81) (1.57) (1.37) F 2,62 = Yers in study, men (SD) 6.38 (1.85) 5.77 (1.86) 6.76 (2.22) F 2,62 = Rce/ethnicity, No. White Blck 1 1 Hispnic 1 2 Asin 1 1 Other/multircil Declined to stte 1 Bseline nnul household income, $, men rnk < > χ 2 8 = χ 2 2 = Declined to stte Bseline dughter WISC score, (7.53) 49.7 (6.3) (6.23) F 2,61 = men (SD) Bseline mother WAIS score, (7.) (5.79) (7.88) F 2,61 = men (SD) Bseline mother eductionl level, men rnk No high school diplom/ged High school diplom/ged 1 2 Some college y College degree y College degree Mster s degree Doctorte χ 2 2 = Decline to stte 1 Clinicl Dt Bseline CDI score, men (SD).88 (1.17) 2.1 (1.62) 2.55 (3.1) F 2,62 = Scn CDI score, men (SD).16 (.47) 1.5 (1.54) 2.8 (2.69) F 2,62 = <.1 Bseline GAF score, men (SD) (5.12) 8.94 (7.8) (7.62) F 2,57 = 1.53 <.1 Scn GAF score, men (SD) 88. (8.44) (6.76) (12.54) F 2,58 = 9.7 <.1 Age of MDE onset, men (SD), y NA NA 15.5 (2.61) NA NA Rte of MDE Recurrence, No. (%) NA NA 8 (4) NA NA Scn psychotropic mediction, No. (%) () 1 (5) 3 (15) Antidepressnt 1 3 Antipsychotic χ 2 2 = Stimulnt Lifetime Clinicl History Mjor depressive disorder 2 NA NA Alcohol use disorder 1 2 NA NA Cnnbis use disorder 1 1 NA NA Socil phobi 4 NA NA Specific phobi 1 1 NA NA Obsessive compulsive disorder NA NA Posttrumtic stress disorder NA NA (continued) jmpsychitry.com (Reprinted) JAMA Psychitry Published online Mrch 21, 218 E5

6 Reserch Originl Investigtion Neurl Mrkers of Resilience in Adolescent Femles t Risk for Mjor Depressive Disorder Tble 1. Demogrphic Informtion nd Clinicl Dt (continued) Vrible CTL (n = 25) RES (n = 2) CVT (n = 2) Sttisticl Vlue P Vlue Generlized nxiety disorder 2 NA NA Anorexi nervos 1 NA NA Bulimi/binge eting disorder 1 1 NA NA Life Events Survey Scores Positive life events, men (SD), 5.88 (2.51) 5.35 (2.83) 5.42 (2.85) F 2,61 = No. Negtive life events, men (SD) 2.88 (2.64) 3.4 (2.58) 4.68 (4.14) F 2,61 = Cumultive positive impct, men 9.44 (4.25) 7.65 (4.23) 8.63 (8.63) F 2,61 = (SD) Cumultive negtive impct, 4.88 (5.46) 6.2 (5.35) 8.55 (8.73) F 2,61 = men (SD) fmri Motion Prmeters Censored No. of volumes, 6.12 (5.46) 4.75 (5.79) 4.25 (3.35) F 2,62 = men (SD) Frme-wise displcement,.7 (.4).9 (.7).9 (.9) F 2,62 = men (SD), mm Frme-wise rottion, men (SD), degrees.2 (.1).3 (.3).2 (.2) F 2,62 = Abbrevitions: CDI, Child Depression Inventory; CTL, control; CVT, converted; fmri, functionl mgnetic resonnce imging; GAF, globl ssessment of functioning score; GED, Generl Eductionl Development; MDE, mjor depressive episode; NA, not pplicble; RES, high-risk resilient; WAIS, Wechsler Adult Intelligence Scle; WISC, Wechsler Intelligence Scle for Children. Discussion Adolescence is neurodevelopmentl period during which experience-dependent plsticity in emotion regultory neurl circuitry my provide opportunities to enhnce resilience. Previous reserch hs focused on neurl substrtes of dolescent depression 4,5 ; in this study, we sought to investigte neurl mrkers of resilience to depression in dolescence. Thus, we compred profiles of functionl connectivity between dolescent femles in the resilient group nd both converted nd control dolescent femles within 3 lrge-scle networks implicted both in dolescent depression nd in emotion regultion: the limbic network, the slience network, nd the executive control network. The resilient group hd notble nd potentilly protective connectivity chrcteristics: compred with converted nd control dolescent femles, dolescent femles in the resilient group exhibited greter connectivity between the mygdl nd prefrontl cortex, with n ssocition between mygdl-ofc connectivity nd the experience of positive life events. Adolescent femles in the resilient group lso showed greter connectivity between regions of the executive control network thn did their converted nd control peers. Finlly, both the converted nd resilient high-risk dolescent femles differed from control dolescent femles in slience network connectivity: converted dolescent femles showed greter intrnetwork connectivity thn did both resilient nd control dolescent femles, nd dolescent femles in the resilient group showed greter connectivity with frontl corticl regions thn did converted dolescent femles. These findings provide insights into brin circuitry tht my be involved in resilience nd, therefore, my inform more effective pproches to the prevention nd tretment of dolescent-onset depression. Severl studies hve found berrnt corticomygdlr connectivity in dolescent femles with depression compred with helthy controls. 14,15 To our knowledge, the present study is the first to exmine the connectivity of this circuit in highrisk dolescent femles in the resilient group. The mygdl plys centrl role in emotion processing, motivtion, nd lerning. 41 We found corticomygdlr connectivity differences in dolescent femles in the resilient group compred with their converted nd control peers. The OFC (encompssed within the prefrontl cortex) undergoes extensive mturtion during dolescence nd is implicted in motivtion, interprettion of ffect, nd emotion regultion. 42 The OFC is lso implicted in modulting mygdl function, 43 with greter positive coupling ssocited with reduced depressive symptomtology over the course of dolescence. 44,45 In this context, greter mygdl-ofc connectivity in the resilient group my serve protective role in behviorl nd emotion regultion tht confers resilience to dolescent femles t risk for depression. We found significnt ssocition between mygdl- OFC connectivity nd positive life events in the dolescent femles in the resilient group only. Although this finding must be replicted in future studies nd we cnnot estblish directionlity of this ssocition, positive life experiences my strengthen mygdl-ofc connectivity or, conversely, greter mygdl-ofc connectivity my led individuls to interpret life events in more positive light. Although specultive, differences in the mening nd interprettion of stressful life events, prticulrly those tht re interpreted s positive, my distinguish high-risk dolescent femles who remin resilient from those who develop MDD. Experience-dependent plsticity my hve prticulrly strong ssocition with brin network connectivity in dolescence. 12 Consequently, the inevitble trnsitions nd life experiences tht occur during dolescence my provide n idel opportunity to dminister trgeted preventions designed to strengthen dptive coping nd cognitive pprisl nd interprettion. Resilient dolescent femles lso showed strong connectivity between regions of the executive control network including the ventrolterl prefrontl cortex, dorsolterl prefrontl cortex, nd temporl regions. This network is implicted in voluntry (ie, explicit) emotion regultion, including cog- E6 JAMA Psychitry Published online Mrch 21, 218 (Reprinted) jmpsychitry.com

7 Neurl Mrkers of Resilience in Adolescent Femles t Risk for Mjor Depressive Disorder Originl Investigtion Reserch Tble 2. Between-Group Connectivity Differences Cluster Size, MNI Coordintes z Scores, Men (SD) Group Chrcteristic mm 3 x y z t Vlue RES CVT CTL RES vs CVT Seed (comprison): left mygdl (RES>CVT) Right superior frontl gyrus t 38 = (.14).15 (.11).1 (.13) Left fusiform gyrus t 38 = (.14).6 (.1).1 (.11) Seed (comprison): right mygdl (RES>CVT) Left orbitofrontl cortex t 38 = (.8).5 (.9).11 (.8) Left inferior temporl gyrus t 38 = (.12).5 (.8).3 (.13) Right inferior temporl gyrus t 38 = (.6).4 (.11).6 (.12) Seed (comprison): left nterior insul (CVT>RES) b Right inferior temporl gyrus t 38 = (.13).2 (.11).8 (.11) Left inferior temporl gyrus t 38 = (.14).6 (.12).8 (.14) Right MD thlmus t 38 = (.17).11 (.7).6 (.1) Right nterior insul t 38 = (.13).54 (.2).21 (.16) Seed (comprison): right nterior insul (RES>CVT) Right superior frontl gyrus t 38 = (.17).4 (.17).8 (.18) Seed (comprison): left dorsolterl prefrontl cortex (RES>CVT) Left ventrolterl PFC (IFG) t 38 = (.16).7 (.14).17 (.11) Seed (comprison): right dorsolterl prefrontl cortex (RES>CVT) Left superior temporl gyrus t 38 = (.9).16 (.12).5 (.18) RES vs CTL Seed (comprison): left mygdl (RES>CTL) c Right ngulr gyrus t 43 = (.13).8 (.18).2 (.13) Seed (comprison): right mygdl (RES>CTL) c Left ngulr gyrus t 43 = (.16). (.16).12 (.15) Seed (comprison): left nterior insul RES>CTL Right middle frontl gyrus t 43 = (.13).3 (.12).4 (.12) Right nterior insul t 43 = (.8).18 (.8).3 (.5) Left precentrl gyrus t 43 = (.12).2 (.15).4 (.9) CTL>RES Left superior frontl gyrus t 43 = (.16).17 (.13).5 (.9) Seed (comprison): right nterior insul (CTL>RES) d Left middle temporl gyrus t 43 = (.17).18 (.12).5 (.14) Right middle temporl gyrus t 43 = (.18).13 (.12).7 (.13) Seed (comprison): right dorsolterl prefrontl cortex (RES>CTL) c Right middle frontl gyrus t 43 = (.17).3 (.18).1 (.17) Abbrevitions: CTL, control; CVT, converted; IFG, inferior frontl gyrus; MD, medil dorsl; MNI, Montrel Neurologicl Institute; PFC, prefrontl cortex; RES, high-risk resilient. No between-group connectivity differences were noted for CVT>RES. b No between-group connectivity differences were noted for RES>CVT. No between-group connectivity differences were noted for CTL>RES. No between-group connectivity differences were noted for RES>CTL. nitive repprisl nd impulse control. Our findings suggest tht high-risk dolescent femles in the resilient group hve greter top-down control over emotions nd behvior thn do high-risk dolescent femles who develop depression. Reserchers hve posited tht dptive selection of goldirected behvior to obtin desired outcome is medited by prefrontl cortex regions within this network 46 ; this provides possible mechnism nd trget through which therpeutic interventions imed t strengthening these connections could increse resilience in high-risk popultions. Greter plsticity within the executive control network following tretment with psychotherpy nd selective serotonin reuptke inhibitors 18-2 my be the bsis of more dptive interprettion of experiences nd emotion regultion. 21,22 Our findings suggest tht this network serves neuroprotective role in dolescence, or lterntively, tht positive life experiences result in enriched executive control network development. Therefore, strengthening executive control network connectivity or providing opportunities for positive life experiences to strengthen connectivity within this network prior to the mni- jmpsychitry.com (Reprinted) JAMA Psychitry Published online Mrch 21, 218 E7

8 Reserch Originl Investigtion Neurl Mrkers of Resilience in Adolescent Femles t Risk for Mjor Depressive Disorder Figure 2. Slience Network Connectivity A Bilterl nterior seeds B Regions of the slience network Right nterior insul Medil dorsl thlmus Right superior frontl gyrus t Vlue b.4 z Score A, Bilterl nterior insul seeds (coordintes in Montrel Neurologicl Institute spce: left: -3, 18, 5; right: 34, 16, 5). B, Regions of the slience network (nterior insul seeds) tht exhibited greter connectivity within the CVT s compred with RES nd CTL groups s well s greter slience network connectivity with the superior frontl gyrus in the RES group. Color br represents t vlues from the between-group pired t tests. B, Box-nd-whisker plots of functionl connectivity quntified s z scores for CTL, CVT, nd RES groups. The horizontl line in the middle of ech box indictes the medin, while the top nd bottom borders mrk the 75th nd 25th percentiles, respectively. The whiskers bove nd below the box mrk the 9th nd 1th percentile. The points beyond the whiskers re outliers. CTL indictes control; CVT, converted; nd RES, high-risk resilient. P <.1 compred with CVT. b P <.1 compred with CVT. Figure 3. Executive Control Network Connectivity A Bilterl DLPFC seeds B Regions of executive control network VLPFC t Vlue.8 z Score Superior temporl gyrus A, Bilterl DLPFC seeds (coordintes in Montrel Neurologicl Institute spce: left: -43, 22, 34; right: 43, 22, 34). B, Regions of executive control network (DLPFC seeds) tht exhibited greter connectivity within the RES compred with CVT nd CTL groups. Color br represents t vlues from the between-group pired t tests. B, Box-nd-whisker plot of functionl connectivity quntified s z scores for CTL, CVT, nd RES groups. The horizontl line in the middle of ech box indictes the medin, while the top nd bottom borders mrk the 75th nd 25th percentiles, respectively. The whiskers bove nd below the box mrk the 9th nd 1th percentile. The points beyond the whiskers re outliers. CTL indictes control; CVT, converted; DLPFC, dorsolterl prefrontl cortex; RES, high-risk resilient; nd VLPFC, ventrolterl prefrontl cortex. P <.1 compred with CVT. E8 JAMA Psychitry Published online Mrch 21, 218 (Reprinted) jmpsychitry.com

9 Neurl Mrkers of Resilience in Adolescent Femles t Risk for Mjor Depressive Disorder Originl Investigtion Reserch festtion of symptoms my increse resilience to dolescentonset depression in high-risk youth. Both high-risk groups (resilient nd converted) differed from controls in slience network connectivity, with the strongest slience network connectivity in the converted group. The slience network is implicted in self-wreness nd in integrting internlly nd externlly slient stimuli. 47 Insul dysfunction is ssocited with negtive interprettion bis of emotions nd life events 16,48 nd is posited to be responsible for misinterpreting slient informtion s negtive. 49 Altered insul responses hve lso been found when dolescent femles with depression view negtive stimuli. 5 Our finding of greter slience network connectivity with frontl regions but less intrnetwork connectivity in resilient thn in converted dolescent femles suggests tht dolescent femles in the resilient group experience negtive processing bises of emotionlly slient informtion but hve compenstory connectivity in executive control network nd frontolimbic regions to counter dverse effects of this processing. Limittions We note severl limittions of this study. First, lthough we monitored this cohort of dolescent femles longitudinlly, we conducted resting-stte scn only t single time. Thus, it is uncler whether the resting-stte functionl connectivity differences between resilient nd converted tht we found in this study were present prior to onset of depression or, lterntively, were consequence of hving developed depression. Exmining bseline or seril resting-stte scns to ssess the trjectory of functionl connectivity over the course of dolescence would lso be informtive to develop ge-specific connectivity profiles reflecting resilience. 51 Second, some of the prticipnts we ctegorized s resilient my experience depression fter ge 18 yers; becuse our study focused on resilience in high-risk dolescent femles, we limited our nlysis to dolescent-onset MDD. Third, only 3 prticipnts with resilience hd pst psychitric dignosis; thus, we could not relibly exmine differences between resilient prticipnts with nd without lifetime history of psychopthology. We were lso unble to exmine group differences in specific life events experienced. Future studies with lrger smple sizes re needed to replicte our findings nd to exmine mechnisms through which intervening life events nd their ttributed mening nd significnce my confer resilience to psychopthology in highrisk individuls. Finlly, while ll of the high-risk dolescent femles hd mothers who hd experienced t lest 2 episodes of MDD during their lifetime, we did not ssess extended fmily history beyond mternl depression. We present dditionl study limittions nd lterntive interprettions in the Supplement (eappendix 5 in the Supplement). Conclusions In this study, we investigted neurl underpinnings of resilience in dolescent femles t fmilil risk for depression nd the influence of positive nd negtively perceived life events. The chrcteristics of brin circuitry implicted in emotion regultion tht we documented pper to be neurl biomrkers of resilience. Our findings suggest n ssocition of experience-dependent plsticity with brin networks, with direct ssocition between positive life events nd mygdlfrontl connectivity in dolescent femles in the resilient group. While further reserch is needed to exmine the neurl bsis of resilience nd whether stronger fmilil risk for depression is ssocited with higher risk of depression in dolescence, the present findings illuminte key functionl connectivity ptterns tht my be trgets for novel prevention nd tretment pproches. By shifting the focus of future reserch to resilience-bsed model of mentl helth, nd by investigting chrcteristics of high-risk individuls who remin resilient, we my increse our understnding of how to optimize resilience to psychopthology. ARTICLE INFORMATION Accepted for Publiction: December 13, 217. Published Online: Mrch 21, 218. doi:1.11/jmpsychitry Author Contributions: Drs Fischer nd Gotlib hd full ccess to ll the dt in the study nd tke responsibility for the integrity of the dt nd the ccurcy of the dt nlysis. Study concept nd design: Fischer, Ho, Gotlib. Acquisition, nlysis, or interprettion of dt: All uthors. Drfting of the mnuscript: Fischer, Cmcho, Ho. Criticl revision of the mnuscript for importnt intellectul content: All uthors. Sttisticl nlysis: All uthors. Obtined funding: Gotlib. Administrtive, technicl, or mteril support: Cmcho, Ho, Gotlib. Study supervision: Gotlib. Conflict of Interest Disclosures: None reported. Funding/Support: Dr Gotlib received support for this reserch from the Ntionl Institute of Mentl Helth grnt R1MH Role of the Funder/Sponsor: The Ntionl Institutes of Helth plyed no role in the study design, collection, mngement, nlysis, interprettion, preprtion, review, interprettion, or submission of this rticle. All uthors report no conflicts of interest to disclose. Disclimer: The content of this mnuscript is solely the responsibility of the uthors nd does not necessrily represent the officil views of the Ntionl Institutes of Helth. Additionl Contributions: We thnk the fmilies who prticipted in this study. We lso thnk Ntlie Colich, PhD, Deprtment of Psychology, Stnford University, nd Srh Ordz, PhD, Deprtment of Psychitry nd Behviorl Sciences, Stnford University, for comments on n erlier drft of this pper. No compenstion ws received. We thnk the stff of the Stnford Neurodevelopment, Affect, nd Psychopthology Lbortory for their help collecting the dt for this study. We thnk Crly Leininger, BA, Citlin Eggleston, BA, Christin Schreiner, BA, Meghn Vinogrd, BA, nd Mri Lemus, BA, for conducting clinicl interviews, nd, Emily Livermore, BA, nd Meghn Vinogrd, BA, for their ssistnce in cquiring the neuroimging dt, for which compenstion ws received. REFERENCES 1. Breslu J, Gilmn SE, Stein BD, Ruder T, Gmelin T, Miller E. Sex differences in recent first-onset depression in n epidemiologicl smple of dolescents. Trnsl Psychitry. 217;7(5):e Heron M. Deths: leding cuses for 214. Ntl Vitl Stt Rep. 216;65(1): Avenevoli S, Swendsen J, He JP, Burstein M, Merikngs KR. Mjor depression in the ntionl comorbidity survey-dolescent supplement: prevlence, correltes, nd tretment. J Am Acd Child Adolesc Psychitry. 215;54(1):37-44.e2. 4. Miller CH, Hmilton JP, Scchet MD, Gotlib IH. Met-nlysis of functionl neuroimging of mjor depressive disorder in youth. JAMA Psychitry. 215;72(1): Kerestes R, Dvey CG, Stephnou K, Whittle S, Hrrison BJ. Functionl brin imging studies of jmpsychitry.com (Reprinted) JAMA Psychitry Published online Mrch 21, 218 E9

10 Reserch Originl Investigtion Neurl Mrkers of Resilience in Adolescent Femles t Risk for Mjor Depressive Disorder youth depression: systemtic review. Neuroimge Clin. 213;4: Americn Psychologicl Assocition. The rod to resilience. -resilience.spx. Accessed Jnury 15, Southwick SM, Bonnno GA, Msten AS, Pnter-Brick C, Yehud R. Resilience definitions, theory, nd chllenges: interdisciplinry perspectives. [published online October 1, 214]. Eur J Psychotrumtol. 214;5. doi:1.342/ejpt.v Romeo RD, McEwen BS. Stress nd the dolescent brin. Ann N Y Acd Sci. 26;194: McEwen BS, Morrison JH. The brin on stress: vulnerbility nd plsticity of the prefrontl cortex over the life course. Neuron. 213;79(1): Giedd JN, Blumenthl J, Jeffries NO, et l. Brin development during childhood nd dolescence: longitudinl MRI study. Nt Neurosci. 1999;2(1): Cunninghm MG, Bhttchryy S, Benes FM. Amygdlo-corticl sprouting continues into erly dulthood: implictions for the development of norml nd bnorml function during dolescence. J Comp Neurol. 22;453(2): McEwen BS. The brin on stress: towrd n integrtive pproch to brin, body, nd behvior. Perspect Psychol Sci. 213;8(6): Perlmn G, Simmons AN, Wu J, et l. Amygdl response nd functionl connectivity during emotion regultion: study of 14 depressed dolescents. J Affect Disord. 212;139(1): Connolly CG, Ho TC, Blom EH, et l. Resting-stte functionl connectivity of the mygdl nd longitudinl chnges in depression severity in dolescent depression. J Affect Disord. 217;27: Cullen KR, Westlund MK, Klimes-Dougn B, et l. Abnorml mygdl resting-stte functionl connectivity in dolescent depression. JAMA Psychitry. 214;71(1): Hmilton JP, Furmn DJ, Chng C, Thomson ME, Dennis E, Gotlib IH. Defult-mode nd tsk-positive network ctivity in mjor depressive disorder: implictions for dptive nd mldptive rumintion. Biol Psychitry. 211;7(4): Ordz SJ, LeMoult J, Colich NL, et l. Rumintive brooding is ssocited with slience network coherence in erly pubertl youth. Soc Cogn Affect Neurosci. 217;12(2): Buchheim A, Vivini R, Kessler H, et l. Chnges in prefrontl-limbic function in mjor depression fter 15 months of long-term psychotherpy. PLoS One. 212;7(3):e Strub J, Plener PL, Sproeber N, et l. Neurl correltes of successful psychotherpy of depression in dolescents. J Affect Disord. 215; 183: To R, Clley CS, Hrt J, et l. Brin ctivity in dolescent mjor depressive disorder before nd fter fluoxetine tretment. Am J Psychitry. 212; 169(4): Erk S, Mikschl A, Stier S, et l. Acute nd sustined effects of cognitive emotion regultion in mjor depression. J Neurosci. 21;3(47): Bermpohl F, Wlter M, Sjonz B, et l. Attentionl modultion of emotionl stimulus processing in ptients with mjor depression ltertions in prefrontl corticl regions. Neurosci Lett. 29;463(2): Crowther A, Smoski MJ, Minkel J, et l. Resting-stte connectivity predictors of response to psychotherpy in mjor depressive disorder. Neuropsychophrmcology. 215;4(7): Clsen PC, Beevers CG, Mumford JA, Schnyer DM. Cognitive control network connectivity in dolescent women with nd without prentl history of depression. Dev Cogn Neurosci. 214;7: Chi XJ, Hirshfeld-Becker D, Biedermn J, et l. Altered intrinsic functionl brin rchitecture in children t fmilil risk of mjor depression. Biol Psychitry. 216;8(11): Blkemore SJ. Development of the socil brin in dolescence. J R Soc Med. 212;15(3): Kufmn J, Birmher B, Brent D, et l. Schedule for Affective Disorders nd Schizophreni for School-Age Children-Present nd Lifetime Version (K-SADS-PL): initil relibility nd vlidity dt. JAm Acd Child Adolesc Psychitry. 1997;36(7): First MB, Spitzer RL, Gibbon M, Willims JB. Structured Clinicl Interview for DSM IV TR Axis I Disorders, Reserch Version, Ptient Edition With Psychotic Screen (SCID-I/P W/ PSY SCREEN). New York, NY: New York Stte Psychitric Institute; Americn Psychitric Assocition. Dignostic nd Sttisticl Mnul of Mentl Disorders: DSM-IV. Wshington, DC: Americn Psychitric Assocition; Kovcs M. Children s Depression Inventory: Mnul. New York: Multi-Helth Systems; Sweringen EM, Cohen LH. Mesurement of dolescents life events: the junior high life experiences survey. Am J Community Psychol. 1985; 13(1): Whitfield-Gbrieli S, Nieto-Cstnon A. CONN: functionl connectivity toolbox for correlted nd nticorrelted brin networks. Brin Connect. 212;2(3): Ho TC, Connolly CG, Henje Blom E, et l. Emotion-dependent functionl connectivity of the defult mode network in dolescent depression. Biol Psychitry. 215;78(9): Hulvershorn LA, Cullen KR, Frncis M, Westlund M. Developmentl Resting Stte Functionl Connectivity for Clinicins. Curr Behv Neurosci Rep. 214;1(3): Cud F, D Agt F, Scco K, Duc S, Geminini G, Vercelli A. Functionl connectivity of the insul in the resting brin. Neuroimge. 211;55(1): Fir DA, Cohen AL, Power JD, et l. Functionl brin networks develop from locl to distributed orgniztion. PLoS Comput Biol. 29;5(5): e Roy AK, Shehzd Z, Mrgulies DS, et l. Functionl connectivity of the humn mygdl using resting stte fmri. Neuroimge. 29;45(2): Mrgulies DS, Kelly AM, Uddin LQ, Biswl BB, Cstellnos FX, Milhm MP. Mpping the functionl connectivity of nterior cingulte cortex. Neuroimge. 27;37(2): Friston KJ, Worsley KJ, Frckowik RS, Mzziott JC, Evns AC. Assessing the significnce of focl ctivtions using their sptil extent. Hum Brin Mpp. 1994;1(3): Siegel JS, Mitr A, Lumnn TO, et l. Dt qulity influences observed links between functionl connectivity nd behvior. Cereb Cortex. 217;27(9): Mers D, Pollrd HB. Network science nd the humn brin: Using grph theory to understnd the brin nd one of its hubs, the mygdl, in helth nd disese. J Neurosci Res. 216;94(6): Vijykumr N, Allen NB, Youssef G, et l. Brin development during dolescence: mixed-longitudinl investigtion of corticl thickness, surfce re, nd volume. Hum Brin Mpp. 216;37(6): Arnsten AF, Rubi K. Neurobiologicl circuits regulting ttention, cognitive control, motivtion, nd emotion: disruptions in neurodevelopmentl psychitric disorders. J Am Acd Child Adolesc Psychitry. 212;51(4): Vijykumr N, Allen NB, Dennison M, Byrne ML, Simmons JG, Whittle S. Cortico-mygdlr mturtionl coupling is ssocited with depressive symptom trjectories during dolescence. Neuroimge. 217;156: Scheuer H, Alrcón G, Demeter DV, Erl E, Fir DA, Ngel BJ. Reduced fronto-mygdlr connectivity in dolescence is ssocited with incresed depression symptoms over time. Psychitry Res. 217;266: Miller EK. The prefrontl cortex nd cognitive control. Nt Rev Neurosci. 2;1(1): Crig AD. How do you feel now? the nterior insul nd humn wreness. Nt Rev Neurosci. 29;1(1): Siegle GJ, Steinhuer SR, Thse ME, Stenger VA, Crter CS. Cn t shke tht feeling: event-relted fmri ssessment of sustined mygdl ctivity in response to emotionl informtion in depressed individuls. Biol Psychitry. 22;51(9): Sliz D, Hyley S. Mjor depressive disorder nd ltertions in insulr corticl ctivity: review of current functionl mgnetic imging reserch. Front Hum Neurosci. 212;6: Henje Blom E, Connolly CG, Ho TC, et l. Altered insulr ctivtion nd incresed insulr functionl connectivity during sd nd hppy fce processing in dolescent mjor depressive disorder. J Affect Disord. 215;178: Gotlib IH, Ordz SJ. The importnce of ssessing neurl trjectories in peditric depression. JAMA Psychitry. 216;73(1):9-1. E1 JAMA Psychitry Published online Mrch 21, 218 (Reprinted) jmpsychitry.com